The major objective of this project is to understand the role of ionotropic glutamate receptors in the cognitive decrements often associated with aging. The first aim includes a determination of the relationship between phosphorylation of NMDA and AMPA receptor subunits and cognitive performance in young and aged rats. Additionally, the level of neurotransmitter release stimulated by NMDA receptors will be examined in young and aged, behaviorally-characterized rats. The second aim characterized the role of phosphorylation of NMDA and AMPA subunits in a specific learning paradigm by using a behavioral/electrophysiological procedure developed by Dr. Eichenbaum which produces learning-related alterations in synaptic efficacy in specific hippocampal pathways. This aim is based on the observation that protein phosphorylation plays an important in LTP and that phosphorylation of specific subunits of ionotropic glutamate receptors subunits appears to be a major mechanism for regulating receptor function. Thus, if phosphorylation is induced by the learning paradigm in young rats, this phenomenon will be examined in aged, behaviorally-characterized rats. The third aim of this project, a collaboration with Drs. Gallagher and McKinney, is to study glucocorticoid receptors and associated transcription factors and their relationship to hippocampal aging. A great deal of evidence implicates dysregulation of glucocorticoids in the negative consequences of aging, particularly in the hippocampus. Experiments are designed to determine if glucocorticoid receptors or APl, which can be associated, are altered in aging and if this alteration is related to cognitive decline. In these studies the parallel to the human condition is clear in that, like the rats used in the experiments, some humans age with little or no loss of cognitive abilities while others tend to have a serious decline in cognition associated with aging. A better understanding of the biochemical events responsible for this difference may lead to novel approaches to alter the age-related cognitive decline.